Pyridopyranoazepine derivatives, their preparation and their therapeutic application

ABSTRACT

The invention relates to pyridopyranoazepine derivatives, to pharmaceutical compositions containing them, to process for preparing them, and to the method of use thereof in the treatment or prevention of disorders associated with a dysfunction of the nicotine receptors.

[0001] The present invention relates to compounds of general formula (I)

[0002] in which

[0003] R₁, is a hydrogen atom, a (C₁-C₄)alkyl group, aphenyl(C₁-C₄)alkyl group, a phenylhydroxy(C₁-C₄)alkyl group, afuranyl(C₁-C₄)alkyl group, or a furanyl-hydroxy(C₁-C₄)alkyl group,

[0004] R₂ is either a hydrogen or halogen atom or a trifluoromethyl,cyano, hydroxyl, nitro, acetyl, (C₁-C₆)alkyl or (C₁-C₆)alkoxy group or agroup of general formula NR₄R₅ in which R₄ is a hydrogen atom or a(C₁-C₄)alkyl or (C₁-C₄)alkanoyl group and R₅ is a hydrogen atom or a(C₁-C₄)alkyl group, or else R₄ and R₅ form, with the nitrogen atom whichcarries them, a C₄-C₇ ring, or a phenyl or naphthyl group optionallysubstituted by a halogen atom or a trifluoromethyl, trifluoromethoxy,cyano, hydroxyl, nitro, acetyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy ormethylenedioxy group linked in the 2 and 3 positions of the phenyl ring,and

[0005] R₃ is a hydrogen or halogen atom or a (C₁-C₄)alkyl group.

[0006] The compounds of general formula (I) can exist in the state ofbases or of addition salts to acids. In addition, the atoms in positions5a and 10a being asymmetric, a compound can exist in the form of puregeometric and optical isomers or of mixtures of the latter.

[0007] According to the invention, it is possible to prepare thecompounds of general formula (I) by a process illustrated by the schemewhich follows.

[0008] A 2-methylpyridin-3-ol of general formula (II), in which R₂ andR₃ are as defined above, is reacted with an alkyllithium, then theintermediate thus obtained is condensed with1-azabicyclo[2.2.2]octan-3-one of formula (III), at low temperature andin an aprotic solvent such as tetrahydrofuran.

[0009] A compound of general formula (IV) is obtained, in which it ispossible, if desired, to introduce or modify the substituents R₂ and R₃according to any method known by the person skilled in the art.

[0010] The compound of general formula (IV) is then subjected to adehydration, which is accompanied by a rearrangement, in acid medium,for example methanesulphonic acid or sulphuric acid at high temperature.

[0011] A compound of general formula (Ia) is obtained, in which it ispossible to modify the R₂ and R₃ substituents and/or to introduce the R₁substituent according to any method known to the person skilled in theart.

[0012] The starting compounds of formulae (II) and (III) arecommercially available (R₂═R₃═H) or can be prepared according to knownmethods.

[0013] The examples which follow illustrate the preparation of somecompounds of the invention. The elemental microanalyses, and the I.R.and N.M.R. spectra, as well as the X-ray diffraction spectra, in certaincases, confirm the structures of the compounds obtained.

[0014] The numbers indicated in brackets in the titles of the examplescorrespond to those of the 1st column of the table given further on.

[0015] In the names of the compounds, the dash “-” is part of the word,and the dash “_” only serves for the splitting at the end of the line;it is to be suppressed in the absence of splitting, and must not bereplaced either by a normal dash or by a space.

EXAMPLE 1

[0016] (Compound No. 1)

(trans)-5a,6,7,9,10,11-Hexahydro-8,10a-methanopyrido_(—)[2′,3′5,6]pyrano[2,3-d]azepineHydrochloride (2:1).

[0017] 1.1.3-[(3-Hydroxypyridin-2-yl)methyl]-1-azabicyclo_(—)[2-2.2.2]octan-3-ol.

[0018] 52.9 g (484 mmol) of 2-methyl-3-hydroxypyridine dissolved in 1300ml of tetrahydrofuran are introduced into a 2000 ml three-neck flaskunder argon. The solution is cooled to −56° C. and 750 ml (975 mmol) ofa 1.3 M 1-methylpropyllithium solution in cyclohexane is added dropwisein the course of 3 h, keeping the temperature lower than −50° C. At theend of the addition, the temperature is allowed to rise to −4° C. in thecourse of 45 min and the mixture is then again cooled to −58° C. to add60.6 g (484 mmol) of 1-azabicyclo[2.2.2]octan-3-one dissolved in 250 mlof tetrahydrofuran dropwise in the course of 40 min. The temperature isallowed to rise to ambient and stirring is maintained for 20 h. Thereaction mixture is cooled to 4° C. and hydrolysed by addition of 110 mlof an aqueous solution of 36% hydrochloric acid. 400 ml of water areadded, the two phases are allowed to settle and the organic phase isextracted with water. The aqueous phases are reunited, the mixture iscooled to 4° C. and a concentrated aqueous solution of sodium hydroxideis added to pH 8.4. The precipitate obtained is filtered and dried invacuo at 80° C. 62.5 g of product are thus obtained.

[0019] Melting point: 270-272° C.

[0020] 1.2.(trans)-5a,6,7,9,10,11-Hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineHydrochloride (2:1).

[0021] 2.34 g (10 mmol) of3-[(3-hydroxypyridin-2-yl)methyl]-1-azabicyclo[2.2.2]octan-3-oldissolved in 10 ml of methanesulphonic acid are introduced into a 50 mlflask and heated at 180° C. for 48 h.

[0022] The reaction mixture is cooled and poured onto ice. It isrendered alkaline by addition of a concentrated aqueous solution ofsodium hydroxide and extracted with chloroform. The organic phase isdried over magnesium sulphate and concentrated under reduced pressure.The residue is purified by chromatography on a silica gel column byeluting with a 90/10/1 mixture of chloroform, methanol and ammonia. Theproduct is obtained in base form, which is salified by addition of asolution of hydrochloric acid in ethanol. 1.55 g of hydrochloride areisolated.

[0023] Melting point: >300° C.

EXAMPLE 2

[0024] (Compound No. 2)

(5AS,10aR)-5a,6,7,9,10,11-Hexahydro-8,10a-methano_pyrido[2′,3′1:5,6]pyrano[2,3-d]azepineHydrochloride (2:1).

[0025] 2.1. (5aS,10aR)-5a,6,7,9,10,11-Hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine

[0026] (3R, 5R)-(—)—O,O′-dibenzoyl-L-tartrate (1.2). 15.335 g (0.0709mol) of(trans)-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepinein 50 ml of ethyl acetate are introduced into a 500 ml flask. A solutionof 50.83 g (0.142 mol) of (3R, 5R)-(—)—O,O′-dibenzoyl-L-tartaric acid in50 ml of ethyl acetate is added, the solvent is evaporated under reducedpressure and the residue is dissolved in 885 ml of a 7/3 mixture ofwater and ethanol at reflux. After cooling, the crystals obtained arecollected by filtration and recrystallized in 50 ml of hot propan-2-ol.

[0027] After cooling, 13.7 g of crystals are obtained Melting point:145-148° C.; [α]_(D) ²⁰=−104.3° (c=0.5, MeOH).

[0028] 2.2. (5aS,10aR)-5a,6,7,9,10,11-Hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineHydrochloride (2:1).

[0029] The treatment of the preceding compound with an aqueous solutionof potassium carbonate followed by an extraction with dichloromethaneallows 3.1 g (0.0143 mol) of compound in base form to be obtained.

[0030] Melting point: 69-71° C.

[0031] [α]_(D) ²⁰=75.4° (c=1, MeOH).

[0032] This base is dissolved in 10 ml of ethanol in a 50 ml flask, 6 ml(0.030 mol) of a solution of 6 M hydrochloric acid in propan-2-ol isadded, the mixture is concentrated to dryness under reduced pressure,the residue is taken up again in 40 ml of propan-2-ol, the mixture isheated to reflux and 5 ml of ethanol are added. After cooling, thecrystals obtained are collected by filtration and dried under reducedpressure.

[0033] 3.4 g of white crystals are obtained.

[0034] Melting point: 330° C.; [α]_(D) ²⁰=−85.3° (c=1, MeOH).

EXAMPLE 3

[0035] (Compound No. 4).

(trans)-2-Bromo-5a,6,7,9,10,11-hexahydro-8,10a-methano_pyrido[2′,3′:5,6]pyrano[2,3-d]azepine.

[0036] 3.1.3-[(6-Bromo-3-hydroxypyridin-2-yl)methyl]-1-azabicyclo[2.2.2]octan-3-ol.

[0037] 52.23 g (0.223 mol) of3-[(3-hydroxypyridin-2-yl)methyl]-1-azabicyclo[2.2.2.]octan-3-olsuspended in 500 ml of water at ambient temperature are introduced intoa 1000 ml flask. 26.7 g (0.669 mol) of sodium hydroxide dissolved in 350ml of water and 26.5 g (0.223 mol) of potassium bromide are added andthe mixture is stirred until dissolution is complete before adding 11.5ml (0.223 mol) of bromine dropwise in the course of 2 h.

[0038] The mixture is stirred for 18 h at ambient temperature, then thereaction mixture is neutralized by addition of 23 ml of acetic acid. Itis cooled in an ice bath and the precipitate obtained is filtered. Themother liquors are concentrated and the precipitate obtained istriturated in propan-2-ol, filtered and rinsed.

[0039] 27.9 g of product are obtained.

[0040] Melting point: 215-221° C.

[0041] 3.2.(trans)-2-Bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine.

[0042] 6.1 g of3-[(6-bromo-3-hydroxypyridin-2-yl)methyl]-1-azabicyclo[2.2.2]octan-3-oland 50 ml of concentrated sulphuric acid are introduced into a 100 mlflask. The mixture is heated at 130° C. for −72 h, then cooled toambient temperature and poured onto ice. The aqueous phase is renderedalkaline to pH 10 by addition of a concentrated aqueous solution ofsodium hydroxide and extracted with chloroform. The organic phases aredried over magnesium sulphate and concentrated under reduced pressure.The residue is purified by chromatography on a silica gel column byeluting with a 90/10/4 mixture of dichloromethane, methanol and ammonia.

[0043] 1.2 g of product are obtained.

[0044] Melting point: 157-159° C.

EXAMPLE 4

[0045] (Compound No. 28).

(trans)-(—)-2-Bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepinehydrobromide (1:1).

[0046] 4.1. (5aS,10aR)-2-Bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine(3R, 5R)-(—)-O,O′-dibenzoyl-L-tartrate (1:2).

[0047] 0.3 g (1 mmol) of(trans)-2-bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepinedissolved in 10 ml of ethyl acetate is introduced into a 50 ml flask,0.358 g (1 mmol) of O,O′-(—)-dibenzoyl-L-tartaric acid dissolved in 3 mlof ethyl acetate is added, the solvent is evaporated under reducedpressure and the residue is recrystallized in 5 ml of hot propan-2-ol.After cooling, the crystals obtained are collected by filtration anddried in vacuo.

[0048] 0.12 g of crystals is obtained.

[0049] Melting point: 200° C.

[0050] [α]_(D) ²⁰=−106° (c=0.5, MeOH).

[0051] 4.2.(trans)-(—)-2-Bromo-5a,6,7,9,10,11-Hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepinehydrobromide (1:1).

[0052] The conversion to the base is carried out by treatment of thepreceding compound with an-aqueous solution of sodium hydroxide,followed by an extraction with dichloromethane. 0.3 g (1 mmol) of baseis dissolved in 30 ml of propan-2-ol in a 100 ml flask. 0.36 ml (2 mmol)of a solution of 33% hydrobromic acid in acetic acid is added. Aftercooling to 4° C., the crystals obtained are collected by filtration anddried in vacuo.

[0053] 0.25 g of white crystals is obtained.

[0054] Melting point: 350-352° C.;

[0055] 76.30 (c=0.5, MeOH).

EXAMPLE 5

[0056] (Compound No. 24).

(trans)-(—)-2-Chloro-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineHydrochloride (2:1).

[0057] 0.2 g (0.68 mmol) of(trans)-(—)-2-bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido_(—)[2′,3′:5,6]pyrano[2,3-d]azepineis dissolved in 4 ml of a concentrated aqueous solution of hydrochloricacid and heated at 180° C. in a sealed tube for 48 h.

[0058] The aqueous phase is evaporated and the residue is recrystallizedin propan-2-ol.

[0059] 0.075 g of crystals is obtained.

[0060] Melting point: 339-344° C.;

[0061] [α]_(D) ²⁰=81° (c=0.5, MeOH)

EXAMPLE 6

[0062] (Compound No. 27).

(trans)-2-Cyano-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineHydrobromide (1:1).

[0063] 0.45 g (1.52 mmol) of(trans)-2-bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineis dissolved in 8 ml of pyridine in a 50 ml flask, 0.205 g (2.29 mmol)of copper cyanide is added and the mixture is heated to reflux for 30 h.75 ml of dichloromethane are added and the organic phase is washed with45 ml of a saturated aqueous solution of ammonium chloride, then with 75ml of water. After drying and concentration of the organic phase underreduced pressure, 0.22 g of expected product is obtained. It isdissolved in propan-2-ol and treated with one equivalent of hydrobromicacid dissolved at 33% in acetic acid. After cooling, collection of thecrystals by filtration and drying in vacuo, 0.21 g of product isobtained.

[0064] Melting point: 329-332° C.

EXAMPLE 7

[0065] (Compound No. 10).

(trans)-2-(4-Methylphenyl)-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepinehydrobromide (2:1).

[0066] 0.3 g (1 mmol) of(trans)-2-bromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepinein 6 ml of toluene, 0.193 g (1.4 mmol) of 4-methylphenylboronic acid,0.072 g (0.06 mmol) of tetrakis(triphenyl)phosphine palladium, 1 ml (2mmol) of sodium carbonate in 2 M aqueous solution and 0.05 ml of ethanolare introduced into a 10 ml reactor, and the reaction mixture is heatedto reflux for 72 h. After settling, the organic phase is placed onsilica gel and eluted with a 97/3/0.3 mixture of dichloromethane,methanol and ammonia.

[0067] 0.31 g of product is obtained which is salified with twoequivalents of hydrobromic acid dissolved in acetic acid.

[0068] Melting point: 355° C.

EXAMPLE 8

[0069] (Compound No. 5)

(trans)-1-Methyl-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineHydrochloride (2:1).

[0070](trans)-5a,6,7,9,10,11-Hexahydro-8,10a-methano_pyrido[2′,3′:5,6]pyrano[2,3-d]azepinein 20 ml of anhydrous tetrahydrofuran is introduced into a 100 mlthree-neck flask, the reaction mixture is cooled to −78° C. to add 1.2ml (3 mmol) of 2.5 M butyllithium in hexane dropwise, and stirring iscontinued at −78° C. for 30 min.

[0071] 0.19 ml (3 mmol) of iodomethane is added and the mixture isallowed to warm slowly to ambient temperature before adding 100 ml ofwater and extracting with dichloromethane. The organic phase is driedover magnesium sulphate, it is evaporated under reduced pressure and theresidue is purified by chromatography on a silica gel column by elutingwith a 90/10/1 mixture of dichloromethane, methanol and ammonia. Theproduct obtained is treated with two equivalents of hydrochloric aciddissolved in propan-2-ol and 0.15 g of crystals is isolated byfiltration.

[0072] Melting point: >330° C.

EXAMPLE 9

[0073] (Compound No. 9).

(trans)-α-Furan-3-yl-5a,6,7,9,10,11-hexahydro-10aH-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine-11-methanolHydrobromide (2:1).

[0074] 0.43 g (2 mmol) of(trans)-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineis treated with furan-3-carboxaldehyde under the conditions described inExample 8.

[0075] After salification with 2 equivalents of hydrobromic acid inacetic acid, 0.3 g of compound is obtained.

[0076] Melting point: 69-73° C. with decomposition.

EXAMPLE 10

[0077] (Compound No. 26).

(trans)-2-4-Dibromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepineHydrobromide (1:1).

[0078] 10.1.3-[(4,6-Dibromo-3-hydroxypyridin-2-yl)methyl]-1-azabicyclo[2.2.2]octan-3-ol.

[0079] A solution of 24 g (0.426 mol) of potassium hydroxide in 600 mlof water is introduced into a 2000 ml flask, 50.0 g (0.213 mol) of3-[(3-hydroxypyridin-2-yl) methyl]-1-azabicyclo[2.2.2.]octan-3-ol, andthen, dropwise in the course of 40 min, a solution of 10.93 ml (0.213mol) of bromine and 152.4 g (1.280 mol) of potassium bromide in 600 mlof water is added, and the mixture is stirred at ambient temperature for16 h. The pH of the mixture is adjusted to 7.5 by addition of aceticacid, and it is stirred for 1 h. It is filtered, the solid obtained isdried, it is taken up in 1000 ml of ethanol, and the suspension obtainedis heated for 2 h.

[0080] After cooling, the precipitate is collected by filtration anddried.

[0081] 21.24 g of solid are obtained.

[0082] Melting point. 260-265° C.

[0083] 10.2.(trans)-2-4-Dibromo-5a,6,7,9,10,11-hexahydro-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]_azepineHydrobromide (1:1).

[0084] 10 g (25 mmol) of3-[(4,6-dibromo-3-hydroxypyridin-2-yl)methyl]-1-azabicyclo[2.2.2]octan-3-olare introduced into a 500 ml flask, 150 ml of concentrated sulphuricacid and 3.6 g (25 mmol) of phosphorus pentoxide are added and themixture is heated at 150° C. for 48 h. It is cooled, poured on to 300 gof ice, the pH is adjusted to 10 by addition of ammonia and the mixtureis extracted with chloroform. The organic phase is dried over sodiumsulphate and filtered, the solvent is evaporated under reduced pressureand the residue is purified by chromatography on a silica gel column byeluting with a 98/2/0.2 mixture of chloroform, methanol and ammonia.

[0085] After salification of the solid obtained with one equivalent ofhydrobromic acid in acetic acid, 3.53 g of hydrobromide are obtained.

[0086] Melting point: 320° C. with decomposition.

[0087] The table which follows illustrates the chemical structures andthe physical properties of some compounds of the invention. In thecolumns, “R₁” and “R₂”, “C₆H₅”, “C₆H₄” and “C₆H₃” denote, respectively,non-substituted, monosubstituted or disubstituted phenyl groups. Thesubstituents and their positions are indicated. “C₄H₃O” denotes afuran-3-yl group. “2-C₁₀H₇” denotes a naphthalen-2-yl group. The column“5a,10a” indicates the configuration of the chiral centres 5a and 10aand “+/−” denotes a racemate. In the column “salt”, “—” denotes acompound in the base state, “HCl” denotes a hydrochloride, “HBr” denotesa hydrobromide, “dbL” denotes a dibenzoyl-L-tartrate and “dbD” denotes adibenzoyl-D-tartrate. The acid:base molar ratios are indicated.

[0088] In the column “M.p. (° C.)”, “(d)” indicates a melting point withdecomposition. TABLE (I)

No. R₁ R₂ R₃ 5a,10a Salt M.p. (° C.) [α]²⁰ _(D) (°)  1 H H H (+/−) HCl2:1 >300 —  2 H H H S,R dbL 1:1 145-148 −104.3 c = 0.5, MeOH — 69-71−75.4 c = 1, MeOH HCl 2:1 330 −85.3 c = 1, MeOH  3 H H H R,S — 69-71 +75c = 1, MeOH  4 H Br H (+/−) — 157-159 —  5 CH₃ H H (+/−) HCl 2:1 >330 — 6 CH₂CH₃ H H (+/−) HBr 2:1 170 (d) —  7 CH₂C₆H₅ H H (+/−) HBr 2:1274-276 —  8 CH(OH)C₆H₅ H H (+/−) HCl 2:1 231-233 —  9 CH(OH)-3-C₄H₃O HH (+/−) HBr 2:1 69-73 (d) — 10 H C₆H₄-4-CH₃ H (+/−) HBr 2:1 355 — 11 HC₆H₅ H (+/−) HBr 1:1 350-359 — 12 H C₆H₄-4-OCF₃ H (+/−) — 120-121 — 13 HC₆H₄-4-CF₃ H (+/−) — 120 — 14 H C₆H₄-3-NO₂ H (+/−) — 203 (d) — 15 HC₆H₄-3-COCH₃ H (+/−) HBr2:1 260 — 16 H C₆H₃-3,4-(OCH₂O) H (+/−) HBr2:1310 — 17 H C₆H₃-3,5-(CF₃)₂ H (+/−) — 102-103 — 18 H C₆H₄-4-F H (+/−) HBr2:1 302 — 19 H C₆H₄-4-C₆H₅ H (+/−) HBr 2:1 350 — 20 H 2-C₁₀H₇ H (+/−) —182 — 21 H Br H − dbL 1:1 200 −106c = 0.7, MeOH 22 H Br H + dbD 1:1214-217 +108c = 0.4, MeOH 23 H Cl H (+/−) HCl 2:1 280-281 — 24 H Cl H −HCl 2:1 339-344 −81c = 0.5, MeOH 25 H Cl H + — 82-85 +94.1c = 0.5, CHCl₃26 H Br Br (+/−) HBr 1:1 320 (d) — 27 H CN H (+/−) HBr 1:1 329-332 — 28H Br H − HBr 1:1 350-352 −76.3c = 0.5, MeOH

[0089] The compounds of the invention have been the subject ofexperiments which have demonstrated their therapeutic properties.

[0090] Thus they have been studied as to their affinity with respect tonicotinic receptors containing the α₄β₂ subunit according to the methodsdescribed by Anderson and Arneric, Eur. J. Pharmacol (1994) 253 261, andby Hall et al., Brain Res. (1993) 600 127. 150 to 200 g male SpragueDawley rats are decapitated and all of the brain is rapidly removed,homogenized in 15 volumes of a 0.32 M sucrose solution at 4° C. and thencentrifuged at 1000 g for 10 min. The pellet is discarded, and thesupernatant is centrifuged at 20,000 g for 20 min at 4° C. The pellet isrecovered and homogenized with the aid of a Polytron™ mill in 15 volumesof-double-distilled water at 4° C., and then centrifuged at 8000 g for20 min. The pellet is discarded and the supernatant and the “buffy coat”are centrifuged at 40,000 g for 20 min, the pellet is recovered,resuspended in 15 ml of double-distilled water at 4° C. and centrifugedonce more at 40,000 g before storing it at −80° C.

[0091] On the day of the experiment, the tissue is slowly thawed andsuspended in 3 volumes of buffer. 150 μl of this membrane suspension areincubated at 4° C. for 120 min in the presence of 100 μl of 1 nM[³H]cytisine in a final volume of 500 μl of buffer, in the presence orabsence of compound to be tested. The reaction is stopped by filtrationon Whatman GF/B™ filters previously treated with polyethyleneimine, thefilters are rinsed with two times 5 ml of buffer at 4° C., and theradioactivity retained on the filter is measured by liquid scintigraphy.The non-specific binding is determined in the presence of 10 μM(−)-nicotine; the non-specific binding represents 75 to 85% of the totalbinding recovered on the filter. For each concentration of compoundstudied, the percentage of inhibition of the specific binding of[³H]cytisine is determined, then the IC₅₀, the concentration of compoundwhich inhibits 50% of the specific binding, is calculated. The IC₅₀values of the most active compounds of the invention are between 0.08and 1 μM.

[0092] The compounds of the invention have also been studied as regardstheir affinity with respect to nicotinic receptors containing the α7subunit, according to the methods described by Marks and Collins, J.Pharmacol. Exp. Ther. (1982) 22 554 and Marks et al., Mol. Pharmacol.(1986) 30 427. 150 to 200 g male OFA rats are decapitated, all of thebrain is rapidly removed, homogenized with the aid of a Polytron™ millin 15 volumes of a 0.32 M sucrose solution at 4° C., then centrifuged at1000 g for 10 min. The pellet is discarded, and the supernatant iscentrifuged at 8000 g for 20 min at 4° C. The pellet is recovered andhomogenized with the aid of a Polytron™ mill in 15 volumes ofdouble-distilled water at 4° C., then centrifuged at 8000 g for 20 min.The pellet is discarded and the supernatant and the “buffy coat” arecentrifuged at 40,000 g for 20 min. The pellet is recovered, resuspendedwith 15 volumes of double-distilled water at 4° C. and centrifuged oncemore at 40,000 g for 20 min before storing it at −80° C. On the day ofthe experiment, the tissue is slowly thawed and suspended in 5 volumesof buffer. 150 μl of this membrane suspension are preincubated at 37° C.for 30 min, in the dark, in the presence or absence of the compound tobe tested. The membranes are then incubated for 60 min at 37° C., in thedark, in the presence of 50 μl of 1 nM [³H]α-bungarotoxin in a finalvolume of 250 μl of 20 mM HEPES buffer with 0.05% of polyethyleneimine.The reaction is stopped by filtration on Whatman GF/C™ filterspreviously treated for 3 hours with 0.5% polyethyleneimine. The filtersare rinsed with two times 5 ml of buffer at 4° C., and the radioactivityretained on each filter is measured by liquid scintigraphy. Thenon-specific binding is determined in the presence of α-bungarotoxin at1 μM final concentration; the non-specific binding representsapproximately 60% of the total binding recovered on the filter. For eachconcentration of compound studied, the percentage of inhibition of thespecific binding of [³H]α-bungarotoxin is determined, then the IC₅₀, theconcentration of compound which inhibits 50% of the specific binding, iscalculated. The IC₅₀ values of the compounds of the invention arebetween 1 and 20 μM.

[0093] The compounds of the invention have likewise been studied asregards their affinity with respect to peripheral nicotinic receptors ofganglionic type according to the method described by Houghtling et al.,Mol. Pharmacol, (1995) 48 280-287.

[0094] The capacity of a compound to displace [³H]-epibatidine frombovine adrenal gland membranes measures its affinity for this receptor.

[0095] Bovine adrenal glands stored at −80° C. are thawed andhomogenized with the aid of a Polytron mill in 20 volumes of 50 mM TrisHCl buffer at pH 7.4 at 4° C., then they are centrifuged at 35,000 g for10 min. The supernatant is discarded and the pellet is resuspended in 30volumes of 50 mM Tris HCl buffer at 4° C. and rehomogenized beforerecentrifuging at 35,000 g for 10 min. The final pellet is taken up in10 volumes of Tris HCl buffer at 4° C. 100 μl of membrane or 10 mg offresh tissue are incubated at 24° C. for 3 h in the presence of 50 μl of0.66 nM [³H]-epibatidine in a final volume of 250 μl of buffer, in thepresence or absence of compound to be tested. The reaction is stopped bydilution of the samples with 50 μM Tris HCl buffer pH 7.4 at 4° C. andthen these are filtered on Whatman GF/C™ filters previously treated for3 hours with 0.5% polyethyleneimine. The filters are rinsed two timeswith 5 ml of buffer and the radioactivity retained on the filter ismeasured by liquid scintigraphy. The non-specific binding is determinedin the presence of (−)nicotine at 2 mM final concentration; thenon-specific binding represents 30 to 40% of the total binding recoveredon the filter. For each concentration of compound studied, thepercentage of inhibition of the specific binding of [³H]-epibatidine isdetermined, then the IC₅₀, the concentration of compound which inhibits50% of the specific binding, is calculated.

[0096] The IC₅₀ values of the most active compounds of the invention arebetween 9 and 20 μM.

[0097] The results of the preceding tests show. that certain compoundsof the invention are selective ligands for the α₄β₂ subunits of thenicotinic receptor.

[0098] The compounds of the invention were finally the subject of invivo experiments which demonstrated their therapeutic properties. Thus,for example, they were studied in the hotplate model, according to themethod of. Eddy and Leimbach, J. Pharmacol. Exp. Ther. (1953) 107385-393 with the aim of investigating and quantifying a possibleanalgesic effect. 20 to 30 g mice were subjected to a heat stimulus bycontact of the paws with a plate maintained at a constant temperature of57.5° C. by a thermostatted water bath. The time of reaction to thepain, which is manifested by licking of the paws or jumping, ismeasured. Thus, after the pretreatment period carried out by thesubcutaneous or oral route (each batch being formed of eight animals forthe same pretreatment), the mice are placed individually on the plateand the time of reaction to the pain is measured. The animal is removedfrom the plate immediately after manifestation of the pain. The maximumtime of exposure to the stimulus is 30 s. The mean reaction timeaccompanied by the standard error of the mean (s.e.m.) is expressed foreach batch. A non-parametric variance analysis (Kruskal-Wallis) iscarried out on the entire batch. A Wilcoxon test allows the comparisonof each treated batch with the control batch. The differences areconsidered as statistically significant at the 5% threshold.

[0099] This reaction time is significantly increased by the analgesicsmainly with central effects.

[0100] The compounds of the invention show an activity in this test atdoses of between 3 and 30 mg/kg by the intraperitoneal or oral route.

[0101] These results suggest the use of the compounds in the treatmentor prevention of disorders associated with a dysfunction of thenicotinic receptors, especially at the level of the central nervoussystem or the gastrointestinal system.

[0102] At the level of the central nervous system, these disorderscomprise cognitive impairments, more specifically memory impairments,but also attention impairments, associated with Alzheimer's disease,with pathological ageing (Age Associated Memory Impairment, AAMI), withParkinson's disease, with mongolism (Down's syndrome), with Korsakoff'salcoholic syndrome, and with vascular dementia (multi-infarct dementia,MID). The compounds of the invention could likewise be useful in thetreatment of the motor disorders observed in Parkinson's disease orother neurological diseases such as Huntington's chorea, Tourette'ssyndrome, tardive dyskinesia and hyperkinesia.

[0103] The compounds of invention can likewise constitute a curative orsymptomatic treatment of cerebral vascular accidents and cerebralhypoxic episodes. They can be used in the case of psychiatricpathologies: schizophrenia, depression, anxiety, panic attacks,compulsive and obsessive behaviour.

[0104] They can prevent the symptoms due to withdrawal from tobacco,alcohol and various substances inducing dependence, such as cocaine,LSD, cannabis and benzodiazepines.

[0105] Finally, they can be used for the treatment of pain.

[0106] At the level of the gastrointestinal system, the compounds of theinvention could be used in the treatment of Crohn's disease, ofulcerative colitis, of irritable bowel syndrome and of obesity.

[0107] To this effect, the compounds of the invention can be present inany form of composition appropriate for enteral, parenteral ortransdermal administration, such as tablets, sugar-coated tablets, hardand soft gelatin capsules, drinkable or injectable suspensions orsolutions such as syrups or ampoules, transdermal patches, etc.,combined with suitable excipients, and dosed to allow a dailyadministration of 0.01 to 20 mg/kg.

1. Compound, in the form of pure geometrical or optical isomers or amixture of such isomers, of general formula (I)

in which R₁ is a hydrogen atom, a (C₁-C₄)alkyl group, a phenyl(C₁-C₄)alkyl group, a phenylhydroxy(C₁-C₄) alkyl group, afuranyl(C₁-C₄)alkyl group, or a furanylhydroxy(C₁-C₄)alkyl group, R₂ iseither a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl,nitro, acetyl, (C₁-C₆)alkyl or (C₁-C₆)alkoxy group or a group of generalformula NR₄R₅ in which R₄ is a hydrogen atom or a (C₁-C₄)alkyl or(C₁-C₄)alkanoyl group and R₅ is a hydrogen atom or a (C₁-C₄)alkyl group,or else R₄ and R₅ form, with the nitrogen atom which carries them, aC₄-C₇ ring, or a phenyl or naphthyl group optionally substituted by ahalogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl,nitro, acetyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or methylenedioxy grouplinked in the 2 and 3 positions of the phenyl ring, and R₃ is a hydrogenor halogen atom or a (C₁-C₄)alkyl group, in the state of a base or anaddition salt to an acid.
 2. Process for preparation of compoundsaccording to claim 1, characterized in that a compound of generalformula (IV)

in which R₂ and R₃ are as defined in claim 1, is subjected to adehydration in acid medium followed by a rearrangement at hightemperature, to obtain a compound of general formula (Ia)

in which, if desired, the substituents R₂ and R₃ are modified and/or asubstituent R₁ such as defined in claim 1 is introduced.
 3. Medicamentcharacterized in that it consists of a compound according to claim
 1. 4.Pharmaceutical composition characterized in that it contains a compoundaccording to claim 1, combined with an excipient.